Galectin 3-binding protein suppresses PRRSV replication via Cullin3-mediated ubiquitination degradation of non-structural protein 12

Porcine reproductive and respiratory syndrome virus (PRRSV) poses a major threat to the global swine industry, yet effective Antiviral strategies remain limited. This study identifies Galectin 3-binding protein (LGALS3BP) as a critical host factor inhibiting PRRSV Infection through targeting the viral conserved non-structural protein 12 (nsp12), a key component of the viral replication-transcription complex. Overexpression of LGALS3BP significantly suppressed PRRSV replication, while its knockdown enhanced viral replication. Mechanistically, LGALS3BP recruits the Cullin3 E3 ubiquitin Ligase via its BACK domain to mediate the ubiquitination of nsp12 at lysine residue 91, leading to proteasomal degradation. This process disrupts nsp12-dependent synthesis of viral subgenomic RNA, thereby disrupting replication. Additionally, LGALS3BP enhances Antiviral innate immunity by upregulating interferon (IFN)-β and IFN-stimulated genes (ISGs). The Antiviral effect of LGALS3BP is conserved across diverse PRRSV strains, highlighting its broad-spectrum potential. These findings reveal a dual mechanism whereby LGALS3BP restricts PRRSV through direct degradation of a critical viral enzyme and modulation of host immune responses, highlighting LGALS3BP as a promising therapeutic avenue for PRRSV control.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) remains a major challenge to global swine production due to its genetic diversity, rapid mutation rate, and ability to evade host immunity. The nsp12 is highly conserved across PRRSV strains and plays a crucial role in viral RNA synthesis. This study identifies LGALS3BP as a critical host factor that inhibits PRRSV Infection by targeting nsp12 via the ubiquitin-proteasome pathway. By uncovering this novel Antiviral mechanism, the research highlights LGALS3BP as a promising therapeutic target for PRRSV control. Moreover, it contributes to our understanding of how host factors modulate viral replication and immunity, opening new avenues for developing host-targeted Antiviral strategies. These findings have the potential to mitigate PRRSV-driven economic losses and improve swine health worldwide.

LGALS3BP; Nsp12; PRRSV; antiviral activity; ubiquitination.